Postoperative Adjuvant Therapy With Tamoxifen, Tegafur Plus Uracil, or Both in Women With Node-Negative Breast Cancer: A Pooled Analysis of
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《临床肿瘤学》
the Collaborative Study Group of Adjuvant Chemo-Endocrine Therapy for Breast Cancer
St Luke’s Hospital, Tokyo
Department of Surgical Oncology, Osaka University Medical School
Osaka Medical Center for Cancer and Cardiovascular Disease, Osaka
Kushiro Rosai Hospital, Kushiro
Fukushima Medical College, Fukushima
Aichi Cancer Center, Nagoya
Kyushu Central Hospital, Fukuoka
Niigata University, Niigata, Japan
ABSTRACT
PURPOSE: This article reports the results of a pooled analysis of six randomized trials conducted to study the efficacy of uracil and tegafur (UFT) in the adjuvant treatment of node-negative breast cancer patients.
PATIENTS AND METHODS: Six randomized controlled trials on node-negative breast cancer patients were conducted from 1992 through 1995 in Japan that included the three, three-arm trials (control [no adjuvant], UFT, and tamoxifen [TAM] groups) and the three, four-arm trials (control, UFT, TAM, and UFT plus TAM groups). Pooled analysis was performed on the data obtained from these six trials (involving 2,934 patients).
RESULTS: Overall survival was compared between the UFT group (including both the UFT group and the TAM plus UFT group) and the non-UFT group (control group and TAM group). A significant difference (P = .04) was observed in 5-year survival rates between the UFT (95.9%) and the non-UFT (94.0%) groups. Overall survival was also compared between the TAM group (TAM group and TAM plus UFT group) and the non-TAM group (control group plus UFT group). The 5-year survival rate (95.2%) in the TAM group was not significantly different from that (93.9%) in the non-TAM group, but the subset analysis showed a significant (P = .01) improvement in the estrogen receptor-positive subset.
CONCLUSION: Adjuvant UFT improves the overall survival of node-negative breast cancer patients. Given that UFT has milder adverse effects, it is suggested that UFT can be a useful alternative to doxorubicin and cyclophosphamide, or cyclophosphamide, methotrexate, and fluorouracil in the adjuvant treatment for node-negative breast cancer.
INTRODUCTION
The introduction of adjuvant chemotherapy such as cyclophosphamide, methotrexate, and fluorouracil (FU; CMF) and anthracycline-containing regimens (doxorubicin and cyclophosphamide [AC]; cyclophosphamide, doxorubicin, and FU [CAF]; cyclophosphamide, epirubicin, and FU [CEF]; and so on) has improved the outcome of node-positive breast cancer patients.1 The sequential or concurrent addition of taxane (paclitaxel or docetaxel) to anthracycline further improves the outcomes in these patients.2–5 Adjuvant chemotherapy has also been shown to improve the outcomes in node-negative breast cancer patients.1 However, the absolute risk reduction of relapse caused by adjuvant chemotherapy is smaller in node-negative patients than that in node-positive patients because of the better prognosis of the tumor, although the incidence and severity of adverse effects is the same in both groups. Japanese node-negative breast cancer patients have a better prognosis than their white counterparts (ie, the 10-year overall survival rate of Japanese node-negative breast cancer patients is approximately 90% by surgery alone, whereas that of white patients is approximately 80%6; thus, the risk-to-benefit ratio of adjuvant chemotherapy merits careful consideration because the absolute risk reduction is probably smaller in Japanese node-negative patients.
The Adjuvant Chemo-Endocrine Therapy for Breast Cancer (ACETBC) trial group in Japan has established adjuvant chemo-endocrine therapy (in particular, the efficacy of adjuvant uracil and tegafur [UFT]) for breast cancer since 1982. UFT is an oral preparation containing tegafur (prodrug of FU) and uracil at the ratio of 1:4. UFT is defined as dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine because uracil inhibits dihydropyrimidine dehydrogenase, which inactivates FU, resulting in the enhancement of FU antitumor activity. UFT is active in a variety of malignant tumors, and shows a response rate of approximately 30% in metastatic breast cancer patients.7,8 In the third ACETBC trial, UFT reduced the risk of recurrence for stage I to IIIA breast cancer patients by 21% (standard deviation [SD], ± 11%), and its effect was more pronounced when it was given for 2 years than 1 year.9
The magnitude of relative risk reduction achieved by UFT was similar to that reported for CMF,1 and the adverse effects of UFT were apparently milder than those of CMF,10,11 suggesting its suitability for use in the adjuvant therapy for node-negative breast cancer patients in Japan, particularly because of the following reasons. Given that the prognosis of Japanese node-negative breast cancer patients is good, the absolute risk reduction achieved by adjuvant therapy for these patients is estimated to be small, if any. The adverse effects seen with CMF therapy, such as leucopenia, alopecia, nausea, and so on, are unlikely to be accepted by most patients with a good prognosis in return for a small reduction in the probability of recurrence. UFT may be more suited for these patients because UFT might confer a risk reduction similar to that of CMF with milder adverse effects. Therefore, in the fourth ACETBC trial, conducted in six districts in Japan, the efficacy of UFT compared with controls (surgery alone) was studied in the adjuvant setting for node-negative breast cancer patients by prospective randomized trials. This article presents the results of a pooled analysis of these six randomized trials.
PATIENTS AND METHODS
Six Randomized Trials Conducted in Six Districts in Japan
The ACETBC trial group performed the fourth series of prospective randomized controlled trials concurrently in six districts of Japan (Hokkaido, Tohoku, Kanto, Chubu, Kinki, and Nishi-Nihon) from 1992 through 1995. In Tohoku, Kanto, and Chubu, three-arm trials were designed to compare the surgery alone group, the surgery plus UFT group (UFT group), and the surgery plus tamoxifen group (TAM group). In Hokkaido, Kinki, and Nishi-Nihon, trials were based on a four-arm design, including an additional surgery plus TAM and UFT group (UFT plus TAM group; Fig 1).
Eligibility Criteria
Outlines of the six trials, which were previously unpublished, are listed in Table 1. All six trials had the same eligibility criteria. Eligible patients had to have histologically confirmed node-negative invasive breast cancer, have clinically measurable lesions 5 cm in diameter, adequate organ function, have undergone mastectomy with axillary node dissection, and be 75 years old. Patients with a history of other cancer therapy (radiotherapy, chemotherapy, endocrine therapy, immunotherapy, and so on) and those with multiple cancers were excluded. Fully informed consent was obtained from all patients before enrollment.
Random Assignment
Patients who met the eligibility criteria were enrolled at a registration center established for each trial. Random assignment was performed by the minimization method12 to ensure that the study groups were comparable with respect to tumor diameter ( 2 v > 2 to 5 cm), estrogen receptor (ER) status (positive v negative v unknown), and age (< 50 v 50 years). The randomization scheme described by Zelen13 was used to adjust for differences among six centers.
Treatment
Patients assigned to receive surgery alone were observed after operation, with no further treatment. Those in the UFT group received 300 mg/d of UFT (or 400 mg/d only in the Hokkaido group) for 2 years, starting within 4 weeks after operation. Patients assigned to the TAM group received 20 mg/d of TAM for 2 years regardless of the ER status. Patients in the UFT plus TAM group received 300 mg/d of UFT (or 400 mg/d only in the Hokkaido group) plus 20 mg/d of TAM for 2 years. In all groups, treatment according to protocol was discontinued on detection of recurrence, and other therapy could be initiated.
Follow-Up
The presence or absence of recurrence was confirmed at regular intervals at each center on the basis of the results of physical examination, chest x-ray films, imaging trials (ultrasonography or computed tomography scan) of the liver, and bone scintigraphic examination.
Adverse reactions were graded according to the WHO toxicity scale. Follow-up surveys were performed in 2002, after at least 6 years had passed since registration in all patients.
ER and DNA Ploidy Determinations
ER status was determined at each center. Either biochemical (enzyme immunoassay) or immunohistochemical techniques could be used.
In some patients, the DNA ploidy pattern of resected tumor tissues was analyzed by flow cytometry. Specimens of each primary breast cancer were frozen in liquid nitrogen in the operating room, and a suspension of isolated nuclei was prepared for DNA ploidy analysis as described by Vindelov et al.14 The suspensions were analyzed with an EPICS MCL-XL flow cytometer (Beckmann Coulter, Miami, FL) interfaced with a computer system (Multiplus; Phoenix Flow Systems, San Diego, CA). Tumors with the G0/G1 and G2/M peaks on the DNA histogram were defined as diploid tumors, and those with a clearly distinct additional peak from the G0/G1 and G2/M peaks were defined as aneuploid tumors. The DNA ploidy pattern was evaluated by an independent panel.
Pooled Analysis
This study consisted of pooled analysis of six randomized controlled trials carried out at the same time and with the same concept in the ACETBC trial groups, and no study was excluded. From February 1992 through April 1995, a total of 2,934 patients were registered. The median duration of observation was 6.2 years. Data from all registered patients were centrally analyzed according to the intention to treat. All analyses were based on individual patient data. Treatment effects were first estimated within each trial and then combined.
The 2 test, Mann-Whitney U test, two sample t test, and analysis of variance were used to determine the statistical significance of differences in baseline characteristics among the treatment groups. Overall survival, the primary end point of the study, was defined as the length of time from surgery to death as a result of any cause. Data on patients who were alive at the time of follow-up were censored. Cumulative 5-year survival rates were estimated according to the Kaplan-Meier method.
A Cox proportional hazards model was used to evaluate response in the drug-treated groups relative to that in the surgery alone group, adjusted for the following variables as covariates: tumor diameter ( 2 v > 2 to 5 cm), ER status (positive v negative v unknown), and age (< 50 v 50 years).
In addition, the overall effect of UFT (surgery alone plus TAM group v UFT group and UFT plus TAM group) and the overall effect of TAM (surgery alone plus UFT group v TAM group and UFT plus TAM group) were analyzed according to the Peto method15 on the basis of odds reduction, after excluding data on the TAM group in the three-arm trials and data on the UFT group in the three-arm trials, respectively. The overall effect of treatment was assessed through a 21 and the heterogeneity between trials through a 2n–1. Tests for interaction were used to detect departures from the homogeneity of treatment effects. Differences between groups in Kaplan-Meier estimates were evaluated with the log-rank test. Relation between rate of first recurrence and treatment were analyzed with the 2 test.
All data were analyzed using SAS software (version 6.12; SAS Institute, Cary, NC). All P values were calculated with two-tailed tests. The significance level was set at 5% for all tests of main effects and 10% for all tests of interaction or heterogeneity.
RESULTS
Comparison of Overall Survival Between Control, UFT, TAM, and UFT Plus TAM Groups
In total, 2,934 patients were analyzed in this pooled analysis including 860 patients in the control group, 860 patients in the UFT group, 865 patients in the TAM group, and 349 patients in the UFT plus TAM group. There was no significant difference in the distribution of clinicopathologic background factors among these four groups (Table 2). The 5-year survival rates were 93.4% for the control group, 96.0% for the UFT group, 95.0% for the TAM group, and 95.7% for the UFT plus TAM group (Fig 2A). Multivariate analysis has shown that the relative risks, taking the risk of the control group as reference, were 0.60 (95% CI, 0.39 to 0.94) for the UFT group, 0.73 (95% CI, 0.48 to 1.11) for the TAM group, and 0.62 (95% CI, 0.34 to 1.14) for the UFT plus TAM group (Table 3).
In the ER-positive subset, 5-year survival rates were 93.5% for the control group, 96.0% for the UFT group, 96.9% for the TAM group, and 98.0% for the TAM plus UFT group (Fig 2B). Multivariate analysis showed that the relative risks were 0.61 (95% CI, 0.33 to 1.13) for the UFT group, 0.44 (95% CI, 0.22 to 0.86) for the TAM group, and 0.28 (95% CI, 0.085 to 0.93) for the TAM plus UFT group (Table 3). In the ER-negative subset, 5-year survival rates were 93.2% for the control group, 95.8% for the UFT group, 93.9% for the TAM group, and 92.8% for the UFT plus TAM group (Fig 2B). Multivariate analysis showed that the relative risks to be 0.59 (95% CI, 0.29 to 1.20) for the UFT group, 0.89 (95% CI, 0.47 to 1.89) for the TAM group, and 1.05 (95% CI, 0.48 to 2.30) for the UFT plus TAM group (Table 3).
Comparison of Overall Survival Between UFT and Non-UFT Groups
We compared overall survival between the UFT group (UFT group and UFT plus TAM group) and the non-UFT group (control group plus TAM group). There was no significant difference in the clinicopathologic background factors between the UFT and the non-UFT groups (Table 4). A significant difference (log-rank test P = .04) was observed in 5-year survival rates between the UFT (95.9%) and the non-UFT (94.0%) groups (Fig 3). The odds reduction by UFT was 35% ± 16%, and no significant heterogeneity was observed among the six trials (Fig 4). In the UFT group, 32 patients died as a result of breast cancer, four died as a result of other types of cancer, and eight died as a result of noncancer diseases. In the non-UFT group, 52 died as a result of breast cancer, nine died as a result of other types of cancer, and five died as a result of noncancer disease. The first recurrent sites are shown in Table 5. The incidence of visceral metastases was significantly (2 test P = .01) lower in the UFT group than the non-UFT group. The subset analysis showed that the effect of UFT was more prominent in patients younger than 50 years (odds reduction, 48%; SD, ± 24%; P = .08) or older than 65 years (odds reduction, 48%; SD, ± 25%; P = .06), and in patients with tumor more than 2 cm in greatest dimension (odds reduction, 37%; SD, ± 18%; P = .06) or with DNA aneuploid tumors (odds reduction, 57%; SD, ± 28%; P = .04), or without TAM (odds reduction, 39%; SD, ± 17%; P = .025; Fig 5). However, interaction tests did not show any significant relationship between those subsets and the therapeutic effectiveness of UFT.
Comparison of Overall Survival Between TAM and Non-TAM Groups
Overall survival was compared between the TAM group (TAM group and UFT plus TAM group) and the non-TAM group (control group plus UFT group). There was no significant difference in the clinicopathologic background factors between the TAM and the non-TAM groups (Table 6). The 5-year survival rate (95.2%) in the TAM group was not significantly different from that (93.9%) in the non-TAM group (Fig 6). In the TAM group, 42 died as a result of breast cancer, three died as a result of other types of cancer, and six died as a result of noncancer diseases. In the non-TAM group, 53 died as a result of breast cancer, nine died as a result of other types of cancer, and five died as a result of noncancer diseases. The first recurrent sites are shown in Table 7. The soft tissue recurrence rate (2.6%) in the TAM group was lower, but not significantly (2 test P = .12) than in the non-TAM group (3.8%). The odds reduction by TAM was 27% (SD, ± 16%), and heterogeneity was not observed among the six trials (Fig 7). Subset analysis showed a significant odds reduction (54%; SD, ± 20%; log-rank test P = .01) in the ER-positive subset but not in the ER-negative subset (2%; SD, ± 27%; log-rank test P = .95), and also that the odds reduction was most prominent in the subset of patients older than 65 years (odds reduction, 45%; SD, ± 25%; P = .08; Fig 8).
Adverse Reactions
Table 8 lists the adverse reactions. The adverse reactions data in the control (surgery alone) group were not included in the table because we had performed a pooled analysis and were looking primarily at effectiveness; thus, we do not have sufficient data on the adverse events in the control group. There were 750 patients with adverse reactions in the UFT group, 743 in the TAM group, and 294 in the UFT plus TAM group, whereas the frequency of grade 2 WHO adverse reactions was 19.5% in the UFT group, 7.8% in the TAM group, and 20.4% in the UFT plus TAM group. Main adverse reactions were liver dysfunction in the TAM group, and liver dysfunction, anorexia, nausea, and vomiting in the UFT group. No increase in toxicity was found in the UFT plus TAM group compared with the UFT group, no increase in toxicity was found in the combined UFT and TAM groups, and there was no thrombosis or severe adverse reactions in any group.
DISCUSSION
One noteworthy observation in the present study is the confirmation of a fairly good prognosis of Japanese node-negative breast cancer patients in the control (surgery alone) group (5-year survival rate, 93.4%) compared with white counterparts (5-year survival rate, approximately 80%). The indications of adjuvant chemotherapy are usually decided on the basis of careful consideration of its risk-benefit balance. Patients with good prognosis can achieve only a small gain in absolute survival rate compared with those with poor prognosis, although the incidence and severity of adverse effects are similar in both groups. Thus, the indication of adjuvant chemotherapy for patients with good prognosis should be considered carefully. In this respect, Japanese node-negative breast cancer patients might be treated somewhat differently from white counterparts with regard to adjuvant chemotherapy.
Recently, oral fluoropyrimidines such as capecitabine (which has been reported to show a higher response rate [30%] than CMF [16%] in metastatic breast cancer patients16) have attracted attention for the treatment of metastatic breast cancer. This observation, taken together with the advantage that capecitabine rarely causes grade 3 to 4 neutropenia, has prompted the use of capecitabine in the adjuvant setting for older women. Actually, Cancer and Leukemia Group B 49907, which is comparing capecitabine with AC or CMF in women older than 65 years, is being conducted in the adjuvant setting for breast cancer. It is of note that the response rate of UFT in the metastatic setting is 30%, which is comparable with reported effectiveness of capecitabine,7,8 and that UFT has a relatively safer profile with regard to adverse reactions in general, and hand-foot syndrome, which appears frequently with capecitabine,17 in particular. These profiles seem to make UFT more appealing in the adjuvant setting.
In addition, we should bear in mind that our study involved much longer periods of administration than the six cycles of 21 days each that are being employed for capecitabine in the adjuvant setting in the ongoing trial (CALGB 49907). However, the administration period of capecitabine in that trial may have been set in accordance with the condition of the control arm of that study, and therefore there is room for doubt about whether six cycles would be optimal for capecitabine administration in an adjuvant setting. Moreover, the failure of 5'-deoxy-5-fluorouridine, which is an intermediate metabolite of capecitabine equipotent to UFT in metastatic disease,18 to demonstrate a survival benefit over surgery alone in Japanese node-negative breast cancer patients may be attributable to the shorter treatment period of 6 months in the adjuvant setting.19
The period of administration of UFT in all six studies was 2 years. The optimal duration of UFT in an adjuvant setting has not been fully clarified, but it is thought that it is necessary to administer it for more than 1 year to maximize benefits.9 The daily dose ranged from 300 to 400 mg in our study. Recently, positive data20 have been presented regarding UFT given in an adjuvant setting to stage I resected adenocarcinoma of the lung, and in that study the dosage of UFT was 260 mg/m2/d (approximately 400 mg/d) for 2 years. On the basis of our results, we recommend dosages of 300 to 400 mg/d.
UFT has been shown to significantly improve the relapse-free survival rates of stage I to IIIA breast cancer patients in the third ACETBC trial.9 Consistent with previous studies, in our pooled analysis of six randomized trials in which only node-negative breast cancer patients were recruited, patients treated with UFT had a significantly (P = .03) better survival rate (96.0%) than the controls (surgery alone; 93.4%). Given that UFT has milder adverse effects than AC and CMF,10,11 UFT may be more suited for the adjuvant treatment of node-negative breast cancer patients.
In ER-positive breast cancer patients, TAM treatment resulted in a significant (P = .02) improvement in survival in comparison with the control (surgery alone), as has been shown repeatedly in previous trials.21 Interestingly, although there was no significant difference, addition of UFT to TAM further improved the 5-year survival rates of ER-positive breast cancer patients (98.0% in the UFT plus TAM group v 96.9% in the TAM group).
Recently, Albain et al22 reported that the outcome of patients treated with concurrent CAF and TAM in the adjuvant setting is significantly poorer than those treated with sequential CAF and TAM, suggesting that TAM might inhibit the antitumor activity of CAF. However, our pooled analysis revealed that UFT has additive effects when given concurrently with TAM. Similarly, the National Surgical Adjuvant Breast and Bowel Project B-20 trial reported that concurrent chemotherapy (CMF, and methotrexate and FU [MF]) plus TAM showed a significantly better survival than TAM alone.23 These inconsistent results seem to suggest that the inhibitory effect of TAM on the antitumor activity of chemotherapy, if any, might depend on the type or duration of chemotherapy.
Comparison of the UFT and non-UFT groups has shown that UFT treatment results in a reduction of relative risk of death by 35%, mainly due to the reduction of visceral metastases, even in Japanese node-negative breast cancer patients who have a fairly good prognosis. Fisher et al24 studied the effect of adjuvant CMF or MF on relapse-free survival in breast cancer patients with good prognosis (node-negative and tumor size < 1 cm) and showed that these adjuvant chemotherapies could significantly improve the relapse-free survival. The 5-year survival rate of the control group of the study by Fisher et al24 was more than 90%—similar to that in our study. Thus, these results indicate that adjuvant chemotherapy is able to improve the survival of breast cancer patients even though they may already have a fairly good prognosis. However, the absolute gain in survival achieved by adjuvant chemotherapy in these patients is relatively small; that is, a 1.9% gain of 5-year survival rate in our study and a 5% gain of 8-year survival rate in the study by Fisher et al24 (chemotherapy plus TAM group v TAM group), and thus, the indications of adjuvant chemotherapy should be carefully selected considering the possibility of adverse effects.
The subset analysis showed that UFT was more effective in tumors measuring more than 2 cm and in aneuploid tumors, suggesting that the risk reduction by UFT is more prominent in tumors with a high risk for recurrence. Another important finding in this study was the demonstration of the usefulness of UFT in patients older than 65 years. However, interaction tests did not show significant differences between these results, and because these are the results of subset analysis, care is required in their interpretation. Randomized trials including a large number of elderly patients (older than 65 years) with node-negative breast cancer have not been conducted sufficiently, thus the indications of adjuvant chemotherapy for these patients are still controversial. In this respect, our study is valuable in that it includes more than 500 patients older than 65 years. Given that UFT shows milder adverse effects than AC and CMF, and because it is reported that 85% of patients opt for oral antitumor agents for chemotherapy rather than intravenous chemotherapy if the efficacy is the same,25 UFT seems to have the potential to be the treatment of choice as the adjuvant therapy for node-negative breast cancer patients, especially for elderly patients in whom dose reduction of AC and CMF is more frequently necessitated due to the adverse effects (eg, neutropenia) than in younger patients.26 Conversely, dose reduction and treatment cessation due to adverse effects are unlikely even in elderly women (older than 65 years) in adjuvant UFT. Currently, a randomized trial (National Surgical Adjuvant Study BC01) comparing UFT with CMF is ongoing in the adjuvant treatment of node-negative breast cancer patients in Japan.11,27 The results of this study together with the CALGB 49907 trial comparing capecitabine with AC or CMF in elderly patients will help to address the role of adjuvant oral fluoropyrimidines in the adjuvant setting.
When this trial was initiated in 1992, it was not established that 5-year TAM was better than 2-year TAM. It was also unclear whether TAM would be effective in ER-negative breast cancer patients; thus, TAM was given regardless of the ER status for 2 years in this study. Consistent with the Early Breast Cancer Trialists' Collaborative Group overview,21 this study has shown that TAM can improve the survival in ER-positive but not ER-negative breast cancer patients. At present, 5-year administration of TAM is considered to be standard care. If 5 years of TAM had been set as a parameter in our study, it is possible that there could have been a significant improvement in the overall survival with TAM. The data from the studies reported in this article cannot incontrovertibly determine whether UFT has additive effect on 5 years of TAM administration, or whether UFT has additive effects on aromatase inhibitors, which may be superior in the adjuvant setting to TAM 28 and is likely to be used increasingly in the future. These issues need to be clarified in a future study.
In conclusion, this pooled analysis has shown that adjuvant UFT can improve the overall survival in node-negative breast cancer patients, and UFT and TAM have the additive positive effects on a survival. Given that UFT has milder adverse effects than AC or CMF, it is suggested that UFT can be a useful alternative to AC or CMF in node-negative breast cancer patients, especially in elderly patients. In addition, in the metastatic setting, concomitant use of docetaxel and capecitabine has been proven to significantly prolong the survival time compared with a single use of docetaxel29; thus, oral fluoropyrimidines seem to have potential to further improve the survival of node-positive breast cancer patients who are treated with adjuvant sequential anthracycline and taxane therapy if fluoropyrimidine is given concurrently with or sequentially to the anthracycline and taxane therapy. This possibility also needs to be investigated in a future study.
Appendix
The following institutions participated in the study. Hokkaido region: First Department of Surgery, Hokkaido University School of Medicine; National Sapporo Hospital; Department of Surgery, Sapporo City General Hospital; Department of Surgery, Iwamizawa Municipal General Hospital; Department of Surgery, Otaru City Hospital; Department of Surgery, Tomakomai City General Hospital; Sapporo-Kosei General Hospital; Sapporo Social Insurance General Hospital; Kohnan Hospital; Department of Surgery, Caress Alliance Tenshi Hospital; Department of Surgery, Nikko Memorial Hospital; Kaisei Hospital; Hokkaido Keiaikai Minami 1-Jyo Hospital; Keiwakai Ebetsu Hospital; Hokuoh Hospital; Department of Surgery, Kucchan-Kosei General Hospital; Tonan Hospital, Federation of National Public Service and Affiliated Personnel Mutual Aid Associations; Shin-Nittetsu Muroran General Hospital; Oji General Hospital; First Department of Surgery, Sapporo Medical University, School of Medicine; Department of Surgery, Sapporo Tetsudo (JR) Hospital; Higashi Sapporo Hospital; Second Department of Surgery, Asahikawa Medical College; Asahikawa City Hospital; Takikawa Municipal Hospital; Fukagawa City Hospital; Department of Surgery, Akabira City General Hospital; Department of Surgery, Asahikawa-Kohsei Hospital; Department of Surgery, Kushiro City General Hospital; Nakashibetsu Town Hospital; Department of Surgery, Kitami Red Cross Hospital; Abasiri-Kosei General Hospital; Department of Surgery, Obihiro-Kosei General Hospital; Department of Surgery, Kushiro Rosai Hospital; Department of Surgery, National Hakodate Hospital; Department of Surgery, Hakodate Central General Hospital; Hakodate Medical Association Hospital.
Tohoku region: First Department of Surgery, Hirosaki University School of Medicine; Second Department of Surgery, Hirosaki University School of Medicine; Hirosaki Hospital; Aomori Prefectural Central Hospital; Hachinohe Red Cross Hospital; Department of Surgery, Aomori City Hospital; Department of Surgery, Hirosaki City Hospital; Aomori-Rosai Hospital; Seihoku Central Hospital; Hachinohe City Hospital; Department of Surgery I, Iwate Medical University; Iwate Prefectural Kitakami Hospital; Division of Surgery, Kitakami Saiseikai Hospital; Second Department of Surgery, Akita University School of Medicine; Hiraka General Hospital; Akita City General Hospital; Nakadori General Hospital; Japanese Red Cross Akita Hospital; Gastroenterological and General Surgery, Department of Organ Function and Controls, Yamagata University School of Medicine; Yamagata Prefectural Central Hospital; Department of Surgery, Municipal Sakata Hospital; Yamagata Prefectural Shinjo Hospital; Okitama Nagai Public Hospital; Yonezawa City Hospital; Division of Gastroenterological Surgery, Graduate School of Medicine Tohoku University; Division of Biologic Regulation and Oncology, Graduate School of Medicine Tohoku University; Division of Advanced Surgical Science and Technology, Graduate School of Medicine Tohoku University; Division of Surgical Oncology, Graduate School of Medicine Tohoku University; Sendai National Hospital; Kesennuma Public Hospital; Miyagi Cancer Center; Miyagi Social Insurance Hospital; Katta Hospital; Shizugawa Public Hospital; Sendai City Hospital; Tohoku Rosai Hospital; Sanuma General Hospital; Department of Surgery, Ishinomaki Red Cross Hospital; Tohoku Welfare Pension Hospital; Furukawa City Hospital; Department of Surgery II, Fukushima Medical University School of Medicine; Ohara General Hospital; Hoshi General Hospital.
Kanto region: Breast Division Department of Surgery School of Medicine, Keio University; Digestive Surgery, Tokyo Medical and Dental University; Third Department of Surgery, Nihon University School of Medicine; Department of Surgery, Tokyo Medical Women's University; Department of Surgery, Tokyo Women's Medical University Daini Hospital; Third Department of Surgery, Tokyo Medical University; Department of Surgery, Jikei University School of Medicine; Department of Surgery, Kyorin University School of Medicine; Ome Municipal General Hospital; Department of Endocrine Surgery, Toranomon Hospital; Kosei General Hospital; Saiseikai Central Hospital; Kitasato Institute Hospital; Department of Endocrine Surgery, Nippon Medical School; Department of Breast and Endocrine Surgery, Juntendo University School of Medicine; Breast and Endocrine Toho University School of Medicine; The Third Department of Surgery Toho University School of Medicine; Tokyo Kosei-Nenkin Hospital; Toshiba Hospital; Tokyo Metropolitan Hiroo General Hospital; Tokyo Kyosai Hospital; Mitsui Memorial Hospital; Kyosai Tachikawa Hospital; National Tokyo Medical Center; Department of Surgery, Kanto Medical Center NTT EC; Department of Surgery, The Jikei Daisan-Hospital; Japanese Red Cross Medical Center; Department of Breast Surgery, Nippon Medical School; Department of Surgery, The Jikei University School of Medicine, Aoto Hospital; Tokyo Metropolitan Fuchuu Hospital; First Department of Surgery, Nihon University School of Medicine; Edogawa Hospital; Akiru Municipal General Hospital; St Luke's International Hospital; Tokyo Electric Hospital; Keiyu Hospital; Department of Surgery, Tokai University School of Medicine; Showa University Fujigaoka Hospital; Hiratsuka City Hospital; Division of Breast and Endocrine Surgery Department of Surgery, St Marianna University School of Medicine; Department of Surgery, Kitasato University School of Medicine; Yokosuka Kyosai Hospital; Nippon Koukan Hospital; Kanto Rosai Hospital; Sagamihara National Hospital; National Yokohama Medical Center; Fujisawa Municipal Hospital; Kanagawa Cancer Center Hospital; St Marianna University School of Medicine Toyoko Hospital; Yamato Municipal Hospital; Yokohama Minami Kyosai Hospital; Nippon Medical School Second Hospital; Isehara Kyodo Hospital; Department of Surgery, Saiseikai Yokohama City Southern Hospital; Saiseikai Kanagawaken Hospital; Seirei Yokohama Hospital; St Marianna University Yokohama City Seibu Hospital; Odawara Municipal Hospital; Sagamihara Kyodo Hospital; Teikyo University Mizonokuchi Hospital; Yokohama Sakae Kyosai Hospital; Yokohama Red Cross Hospital; Department of Academic Surgery, Chiba University Graduate School of Medicine; Department of Surgery, Kameda General Hospital; Department of General Surgery, Chiba University Graduate School of Medicine; Department of Surgery, Matsudo Municipal Hospital; Department of Surgery, Teikyo University School of Medicine Ichihara Hospital; Kohnodai Hospital, National Center of Neurology and Psychiatry; Department of Surgery, Chiba Rousai Hospital; Department of Surgery, Jikei University Kashiwa Hospital; Department of Surgery, Sakura Hospital Toho University School of Medicine; Second Department of Surgery, Saitama Medical School; Division of Breast Surgery, Saitama Cancer Center; Kasukabe Municipal Hospital; Saitama Social Insurance Hospital; National Saitama Hospital; Saitama Red Cross Hospital; First Department of Surgery, Saitama Medical School; Koshigaya Municipal Hospital; Koshigaya Hospital Dokkyo University School of Medicine; Ageo Central General Hospital; Souka Municipal Hospital; Gunma Prefectural Cancer Center; Takasaki National Hospital; National Nishigunma Hospital; Sano Kousei General Hospital; First Department of Surgery, Dokkyo University School of Medicine; Ashikaga Red Cross Hospital; Haga Red Cross Hospital; Kamitsuga General Hospital; Department of Surgery, Tochigi Cancer Center; Department of Surgery, Mito Red Cross Hospital; Department of Surgery, Mito National Hospital; Department of Surgery, Toride Kyodo General Hospital; The First Department of Surgery, Faculty Medicine University of Yamanashi; The Second Department of Surgery, Faculty Medicine University of Yamanashi; Ojiya General Hospital; Department of Surgery, Shizuoka Red Cross Hospital.
Chubu region: The Second Department of Surgery, Nagoya University School of Medicine; The Second Department of Surgery, Nagoya City University Medical School; Department of Surgery, School of Medicine Fujita Health University; The First Department of Surgery, Aichi Medical University; National Nagoya Hospital; Second Teaching Hospital School of Medicine Fujita Health University; Department of Surgery, Nagoya First Red Cross Hospital; Department of Surgery, Nagoya Second Red Cross Hospital; Johoku Municipal Hospital; Higashi Municipal Hospital of Nagoya; Kasugai Municipal Hospital; Toyohashi Municipal Hospital; Department of Surgery, Toyokawa City Hospital; Okazaki City Hospital; Nishio Municipal Hospital; Nagoya Ekisaikai Hospital; Seirei Hospital; Chubu Rosai Hospital; Department of Surgery, NTT West Corporation Tokai General Hospital; Tosei General Hospital; Department of Surgery, Kamo Hospital; Toyota Memorial Hospital; Showa Hospital; Moriyama Municipal Hospital, City of Nagoya; Department of Surgery, Gamagori City Hospital; Department of Surgery, Anjo Kosei Hospital; Department of Surgery, Chita City Hospital; Department of Advanced Surgery, Gifu University School of Medicine; Department of Surgical Oncology, Gifu University School of Medicine; Department of Surgery, Gifu Prefectural Gifu Hospital; Gifu Prefectural Tajimi Hospital; Department of Surgery, Ogaki Municipal Hospital; Department of Surgery, Gifu Municipal Hospital; Department of Surgery, Kumiai Hospital; Department of Surgery, Ibi General Hospital; Department of Surgery, Toki General Municipal Hospital; Department of Surgery, National Matsumoto Hospital; Department of Surgery, Nagano Red Cross Hospital; Department of Surgery, Okaya Enrei Hospital; Department of Surgery, Komoro Kosei Hospital; Department of Surgery, Iida Municipal Hospital; Showa Inan Hospital; Department of Surgery, Nagano Chuo Hospital; Department of Surgery, Iiyama Red Cross Hospital; Department of Surgery, Nagano Prefectural Welfare Federation of Agricultural Cooperatives Hokushin General Hospital; Department of Surgery, Toyoshina Red Cross Hospital; The First Department of Surgery, Faculty of Medicine, Mie University; The Second Department of Surgery, Faculty of Medicine, Mie University; Department of Surgery, National Mie Chuo Hospital; Department of Surgery, Yamada Red Cross Hospital; Department of Surgery, Matsusaka Chuo General Hospital; Mie Prefectural Shima Hospital; Department of Surgery, Ise Municipal General Hospital; Department of Surgery, Yokkaichi Municipal Hospital; Department of Surgery, Matsusaka City Hospital; The Department of General Surgery, Suzuka General Hospital; Department of Surgery, Saiseikai Matsusaka General Hospital; Yamamoto General Hospital; Department of Surgery, Yokkaichi Social Insurance Hospital; First Department of Surgery, Hamamatsu University School of Medicine; Tosei National Hospital; Department of Surgery, Shizuoka General Hospital; Fukuroi Municipal Hospital; Yaizu City Hospital; Hamamatsu Medical Center; Fuji City General Hospital; Seirei mikatahara Hospital; Seirei Hamamatsu General Hospital; Ensyu General Hospital; Shizuoka Kosei General Hospital; Seirei Numazu Hospital; Fujinomiya City General Hospital; Second Department of Surgery, Toyama Medical and Pharmaceutical University; Kurobe City Hospital; Department of Surgery, Kouseiren Takaoka Hospital; Tonami General Hospital; Department of Surgery (I), Kanazawa University School of Medicine; Department of Surgery II, Kanazawa University Hospital; Kanazawa Social Insurance Hospital; Kanazawa Social Insurance Hospital; Department of Surgery II, University of Fukui; Fukui Red Cross Hospital; Fukui Prefectural Hospital; First Department of Surgery, Faculty of Medicine, University of Fukui.
Kinki region: Second Department of Surgery, Osaka City University Medical School; Department of Surgery E1, Osaka University Graduate School of Medicine; Department of Surgery and Clinical Oncology, Osaka University Graduate School of Medicine; Department of Surgical Oncology, Osaka University Graduate School of Medicine; Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases; Department of General and Gastrointestinal Surgery, Osaka Medical College; Osaka Kaisei Hospital; Osaka Police Hospital; Osaka Seamen's Insurance Hospital; Osaka Railway Hospital of West Japan Company; Osaka Red Cross Hospital; Osaka General Medical Center; Osaka Rosai Hospital; Department of Surgery, Kansai Medical University; Kitano Hospital; Osaka National Hospital; Hanwadainisenboku Hospital; PL Hospital; Nissay Hospital; Ikeda Municipal Hospital; Sakai Municipal Hospital; Toyonaka Municipal Hospital; Higashiosaka City General Hospital; Minoh City Hospital; Yao Municipal Hospital; Yodogawa Christian Hospital; Wakayama Medical University Surgery I; Wakayama Rosai Hospital; Department of Surgical Oncology, Osaka City University Graduate School of Medicine; Saiseikai Tondabayasi Hospital; Rinku General Medical Center; Sakai Hospital, Kinki University School of Medicine; Mimihara General Hospital; Kaizuka City Hospital; Kishiwada City Hospital; Bell Land General Hospital; Otemae Hospital; Minami Wakayama National Hospital; Hirakata City Hospital; Hanwasumiyoshi General Hospital; First Department of Surgery, Hyogo College of Medicine; Hyogo College of Medicine Second Department of Surgery; Hyogo Prefectural Amagasaki Hospital; Hyogo Prefectural Tsukaguchi Hospital; Hyogo Prefectural Nishinomiya Hospital; Nishinomiya Municipal Central Hospital; Kansai Rosai Hospital; Kawanishi City General Hospital; Kobe City General Hospital; Konan Hospital; Shinko Hospital; Department of Gastroenterological Surgery Graduate School of Medical Sciences Kobe University; National Kobe Hospital; Kobe West City Hospital; Akashi Municipal Hospital; Kawasaki Hospital; National Himeji Hospital; Hyogo Prefectural Kakogawa Hospital; Takasago Municipal Hospital; Ako City Hospital; Toyooka Hospital; Kinki Central Hospital of The Mutual Aid Association of Public School Teachers; Kobe Ekisaikai Hospital; Rokko Hospital; School of Health Sciences Faculty of Medicine Kyoto University; Kyoto Prefectural University of Medicine; Kyoto First Red Cross Hospital; Kyoto National Hospital; Department of Surgery, Kyoto City Hospital; Uji Hospital; Koseikai Takeda Hospital; National Maizuru Hospital; Nantan General Hospital; Fukuchiyama City Hospital; Kyoto Prefectural Yosanoumi Hospital; Kyoto Senbai Hospital; Maizuru Municipal Hospital; Federation of National Public Service Personnel Mutual Aid Associations Maizuru Kyosai Hospital; Department of Surgery, Shiga University of Medical Science; Nagahama City Hospital; First Department of Surgery, Nara Medical University; National Nara Hospital; Saiseikai Chuwa Hospital; Saiseikai Shiga Hospital; Kansai Medical University Otokoyama Hospital; Department of Breast and Thyroid Surgery, Kawasaki Medical School; Kurashiki Medical Center.
Nishi-Nihon region: Department of Surgery Division of Frontier Medical Science Program for Biomedical Research Graduate School of Biomedical Science Hiroshima University; Hiroshima Prefectural Hospital; Hiroshima Red Cross Hospital and Bomb Survivors Hospital; National Kure Medical Center; Hiroshima City Asa Hospital; Miyoshi Central Hospital; Fukuyama National Hospital; Department of Surgery Division of Clinical Medical Science Program for Applied Biomedicine Graduate School of Biomedical Science Hiroshima University; Department of Surgical, Oncology Research Institute for Radiation Biology and Medicine Hiroshima University; Hiroshima Municipal Hospital; Hiroshima General Hospital; Chugoku Central Hospital; Okayama Saiseikai General Hospital; Kurashiki Central Hospital; National Okayama Medical Center; Department of Gastroenterological Surgery, Transplant and Surgical Oncology, Okayama University Graduate School of Medicine and Dentistry; Department of Surgery, Division of Surgical Oncology, School of Medicine, Tottori University; Tottori Municipal Hospital; Yamaguchi Rosai Hospital; Shimonoseki National Hospital; Shiminoseki Kosei Hospital; Shimonoseki City Central Hospital; Iwakuni National Hospital; Department of Digestive Surgery and Surgical Oncology, Molecular Science and Applied Medicine, Yamaguchi University School of Medicine; Tagawa City Hospital; Saiseikai Yahata General Hospital; Department of Surgery and Science, Graduate School of Medical Science, Kyushu University; National Kyushu Cancer Center; First Department of Surgery, Fukuoka University School of Medicine; National Kyushu Medical Center; First Department of Surgery, Kurume University School of Medicine; Aso Iizuka Hospital; Syakaihoken Nakabaru Hospital; Fukuoka City Hospital; Fukuoka-Higashi National Hospital; Munakata Medical Association Hospital; Saga Prefectural Hospital Kouseikan; Department of Transplantation and Digestive Surgery Nagasaki University Graduate School of Biomedical Sciences; National Nagasaki Medical Center; The Japanese Red Cross Nagasaki Atomic Bomb Hospital; Nagasaki Municipal Hospital; Division of Surgical Oncology, Department of Translational Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences; Division of Surgical Oncology, Kyushu University Hospital at Beppu; Oita Red Cross Hospital; Oita Prefectural Hospital; Department of Surgery II, Miyazaki Medical College; National Hospital Organization Miyakonojo Hospital; Miyazaki Prefectural Nichinan Hospital; Kumamoto Chuou Hospital; Saiseikai Kumamoto Hospital; Kumamoto Rousai Hospital; Minamata City General Hospital and Medical Center; Arao Municipal Hospital; Yamaga Municipal Hospital; Yatsushiro Health Insurance General Hospital; Kumamoto City Hospital; Tamana Central Hospital; Kanoya Medical Center Ctizens' Health Plaza; Department of Surgical Oncology and Digestive Surgery, Field of Oncology, Course of Advanced Therapeutics, Kagoshima University Graduate School of Medical and Dental Sciences; Saisekai Sendai Hospital; Unit of Organ-Oriented Medicine, Division of Digestive and General Surgery, Faculty of Medicine, University of The Ryukyus; Department of Bioregulatory Medicine, Thoracic and Cardiovascular Surgery Division, Faculty of Medicine, University of The Ryukyus; Okinawa Red Cross Hospital; Department of Oncological and Regenerative Surgery, School of Medicine, University of Tokushima; Tokushima City Hospital; Kagawa Prefectural Central Hospital; Takamatsu Red Cross Hospital; Surgery I, Ehime University Hospital; Matsuyama Red Cross Hospital; National Shikoku Cancer Center; Department of Surgery, Kochi Medical School; Kochi Red Cross Hospital; Kochi Municipal Central Hospital; Oikawa Hospital; Kitakyushu City Yahata Hospital; Department of Surgery II, University of Occupational and Environmental Health; Nippon Steel Yawata Memorial Hospital; Kitakyushu Municipal Medical Center, Japan.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Acknowledgment
We thank J. Patrick Barron of the International Medical Communications Center of Tokyo Medical University for his review of this manuscript.
NOTES
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
Early Breast Cancer Trialists' Collaborative Group: Polychemotherapy for early breast cancer: An overview of the randomised trials. Lancet 352:930-942, 1998
Henderson IC, Berry DA, Demetri GD, et al: Improved outcomes from adding sequential Paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21:976-983, 2003
Citron ML, Berry DA, Cirrincione C, et al: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 21:1431-1439, 2003
Nabholtz JM, Pienkowski T, Mackey T, et al: Phase III trial comparing TAC (docetaxel, doxorubicin, cyclophosphamide) with FAC (5-fluorouracil, doxorubicin, cyclophosphamide) in the adjuvant treatment of node positive breast cancer (BC) patients: Interim analysis of the BCIRG 001 study. Proc Am Soc Clin Oncol 21:35a, 2002 (abstr 137)
Mamounas EP, Bryant J, Lembersky BC, et al: Paclitaxel (T) following doxorubicin/cyclophosphamide (AC) as adjuvant chemotherapy for node-positive breast cancer: Results from NSABP B-28. Proc Am Soc Clin Oncol 22:4, 2003 (abstr 12)
Nemoto T, Tominaga T, Chamberlain A, et al: Differences in breast cancer between Japan and the United States. J Natl Cancer Inst 58:193-197, 1977
Ota K, Taguchi T, Kimura K: Report on nationwide pooled data and cohort investigation in UFT phase II study. Cancer Chemother Pharmacol 22:333-338, 1988
Tashiro H, Nomura Y, Ohsaki A: A double blind comparative study of tegafur (FT) and UFT (a combination of Tegafur and uracil) in advanced breast cancer. Jpn J Clin Oncol 24:212-217, 1994
Kasumi F, Yoshimoto M, Uchino J, et al: Meta-analysis of five studies on tegafur plus uracil (UFT) as post-operative adjuvant chemotherapy for breast cancer. Oncology 64:146-153, 2003
Tamura H, Kojima M, Kobayashi H, et al: Randomized comparative study of CMF (cyclophosphamide, methotrexate and 5-fluorouracil) and UFT-tamoxifen regimens as adjuvant chemotherapy after surgery for breast cancer: Tochigi Prefectural Study Group for Post-Breast Cancer Adjuvant Chemotherapy [in Japanese]. Gan To Kagaku Ryoho 27:993-1002, 2000
Shimozuma K, Ohashi Y, Watanabe T, et al: Impact of surgical adjuvant chemotherapy on health-related quality of life of patients with breast cancer in the first-year of treatment—A phase III randomized trial comparing uracil/tegafur with CMF in high-risk node-negative patients (N-SAS BC 01). Proc Am Soc Clin Oncol 22:55, 2003 (abstr 220)
Pocock SJ, Simon R: Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Biometrics 31:103-115, 1975
Zelen M: The randomization and stratification of patients to clinical trials. J Chronic Dis 27:365-375, 1974
Vindelov LL: Flow cytometric DNA analysis. Eur J Respir Dis 66:313-314, 1985
Early Breast Cancer Trialists' Collaborative Group: Treatment of Early Breast Cancer, Vol 1.1. Oxford, United Kingdom, Oxford University Press, 1990, pp 12-18
O'Shaughnessy JA, Blum J, Moiseyenko V, et al: Randomized, open-label, phase II trial of oral capecitabine (Xeloda) vs. a reference arm of intravenous CMF (cyclophosphamide, methotrexate and 5-fluorouracil) as first-line therapy for advanced/metastatic breast cancer. Ann Oncol 12:1247-1254, 2001
Blum JL, Jones SE, Buzdar AU, et al: Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 17:485-493, 1999
Niitani H, Kimura K, Saito T, et al: Phase II study of 5'-deoxy-5-fluorouridine (5'-DFUR) in patients with malignant cancer: A multi-institutional cooperative study [in Japanese]. Gan To Kagaku Ryoho 12:2044-2051, 1985
Tominaga T, Toi M, Abe O, et al: The effect of adjuvant 5'-deoxy-5-fluorouridine in early stage breast cancer patients: Results from a multicenter randomized controlled trial. Int J Oncol 20:517-525, 2002
Kato H, Ichinose Y, Ohta M, et al: A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N Engl J Med 350:1713-1721, 2004
Early Breast Cancer Trialists' Collaborative Group: Tamoxifen for early breast cancer: An overview of the randomised trials. Lancet 351:1451-1467, 1998
Albain KS, Green SJ, Ravdin PM, et al: Adjuvant chemohormonal therapy for primary breast cancer should be sequential instead of concurrent: Initial results from intergroup trial 0100 (SWOG-8814). Proc Am Soc Clin Oncol 21:37a, 2002 (abstr 143)
Fisher B, Dignam J, Wolmark N, et al: Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst 89:1673-1678, 1997
Fisher B, Dignam J, Tan-Chiu E, et al: Prognosis and treatment of patients with breast tumors of one centimeter or less and negative axillary lymph nodes. J Natl Cancer Inst 93:112-120, 2001
Borner MM, Schoffski P, de Wit R, et al: Patient preference and pharmacokinetics of oral modulated UFT versus intravenous fluorouracil and leucovorin: A randomised crossover trial in advanced colorectal cancer. Eur J Cancer 38:349-358, 2002
Crivellari D, Bonetti M, Castiglione-Gertsch M, et al: Burdens and benefits of adjuvant cyclophosphamide, methotrexate, and fluorouracil and tamoxifen for elderly patients with breast cancer: The International Breast Cancer Study Group Trial VII. J Clin Oncol 18:1412-1422, 2000
Watanabe T: Phase III randomized comparison of postoperative adjuvant chemotherapy with 2-year oral uracil/tegafur versus 6-cycle cyclophosphamide/methotrexate/5-fluorouracil in high-risk node-negative breast cancer patients. Cancer Chemother Pharmacol 42:S68-S70, 1998 (suppl)
Baum M, Budzar AU, Cuzick J, et al: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: First results of the ATAC randomised trial. Lancet 359:2131-2139, 2002
O'Shaughnessy J, Miles D, Vukelja S, et al: Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: Phase III trial results. J Clin Oncol 20:2812-2823, 2002(Shinzaburo Noguchi, Hirok)
St Luke’s Hospital, Tokyo
Department of Surgical Oncology, Osaka University Medical School
Osaka Medical Center for Cancer and Cardiovascular Disease, Osaka
Kushiro Rosai Hospital, Kushiro
Fukushima Medical College, Fukushima
Aichi Cancer Center, Nagoya
Kyushu Central Hospital, Fukuoka
Niigata University, Niigata, Japan
ABSTRACT
PURPOSE: This article reports the results of a pooled analysis of six randomized trials conducted to study the efficacy of uracil and tegafur (UFT) in the adjuvant treatment of node-negative breast cancer patients.
PATIENTS AND METHODS: Six randomized controlled trials on node-negative breast cancer patients were conducted from 1992 through 1995 in Japan that included the three, three-arm trials (control [no adjuvant], UFT, and tamoxifen [TAM] groups) and the three, four-arm trials (control, UFT, TAM, and UFT plus TAM groups). Pooled analysis was performed on the data obtained from these six trials (involving 2,934 patients).
RESULTS: Overall survival was compared between the UFT group (including both the UFT group and the TAM plus UFT group) and the non-UFT group (control group and TAM group). A significant difference (P = .04) was observed in 5-year survival rates between the UFT (95.9%) and the non-UFT (94.0%) groups. Overall survival was also compared between the TAM group (TAM group and TAM plus UFT group) and the non-TAM group (control group plus UFT group). The 5-year survival rate (95.2%) in the TAM group was not significantly different from that (93.9%) in the non-TAM group, but the subset analysis showed a significant (P = .01) improvement in the estrogen receptor-positive subset.
CONCLUSION: Adjuvant UFT improves the overall survival of node-negative breast cancer patients. Given that UFT has milder adverse effects, it is suggested that UFT can be a useful alternative to doxorubicin and cyclophosphamide, or cyclophosphamide, methotrexate, and fluorouracil in the adjuvant treatment for node-negative breast cancer.
INTRODUCTION
The introduction of adjuvant chemotherapy such as cyclophosphamide, methotrexate, and fluorouracil (FU; CMF) and anthracycline-containing regimens (doxorubicin and cyclophosphamide [AC]; cyclophosphamide, doxorubicin, and FU [CAF]; cyclophosphamide, epirubicin, and FU [CEF]; and so on) has improved the outcome of node-positive breast cancer patients.1 The sequential or concurrent addition of taxane (paclitaxel or docetaxel) to anthracycline further improves the outcomes in these patients.2–5 Adjuvant chemotherapy has also been shown to improve the outcomes in node-negative breast cancer patients.1 However, the absolute risk reduction of relapse caused by adjuvant chemotherapy is smaller in node-negative patients than that in node-positive patients because of the better prognosis of the tumor, although the incidence and severity of adverse effects is the same in both groups. Japanese node-negative breast cancer patients have a better prognosis than their white counterparts (ie, the 10-year overall survival rate of Japanese node-negative breast cancer patients is approximately 90% by surgery alone, whereas that of white patients is approximately 80%6; thus, the risk-to-benefit ratio of adjuvant chemotherapy merits careful consideration because the absolute risk reduction is probably smaller in Japanese node-negative patients.
The Adjuvant Chemo-Endocrine Therapy for Breast Cancer (ACETBC) trial group in Japan has established adjuvant chemo-endocrine therapy (in particular, the efficacy of adjuvant uracil and tegafur [UFT]) for breast cancer since 1982. UFT is an oral preparation containing tegafur (prodrug of FU) and uracil at the ratio of 1:4. UFT is defined as dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine because uracil inhibits dihydropyrimidine dehydrogenase, which inactivates FU, resulting in the enhancement of FU antitumor activity. UFT is active in a variety of malignant tumors, and shows a response rate of approximately 30% in metastatic breast cancer patients.7,8 In the third ACETBC trial, UFT reduced the risk of recurrence for stage I to IIIA breast cancer patients by 21% (standard deviation [SD], ± 11%), and its effect was more pronounced when it was given for 2 years than 1 year.9
The magnitude of relative risk reduction achieved by UFT was similar to that reported for CMF,1 and the adverse effects of UFT were apparently milder than those of CMF,10,11 suggesting its suitability for use in the adjuvant therapy for node-negative breast cancer patients in Japan, particularly because of the following reasons. Given that the prognosis of Japanese node-negative breast cancer patients is good, the absolute risk reduction achieved by adjuvant therapy for these patients is estimated to be small, if any. The adverse effects seen with CMF therapy, such as leucopenia, alopecia, nausea, and so on, are unlikely to be accepted by most patients with a good prognosis in return for a small reduction in the probability of recurrence. UFT may be more suited for these patients because UFT might confer a risk reduction similar to that of CMF with milder adverse effects. Therefore, in the fourth ACETBC trial, conducted in six districts in Japan, the efficacy of UFT compared with controls (surgery alone) was studied in the adjuvant setting for node-negative breast cancer patients by prospective randomized trials. This article presents the results of a pooled analysis of these six randomized trials.
PATIENTS AND METHODS
Six Randomized Trials Conducted in Six Districts in Japan
The ACETBC trial group performed the fourth series of prospective randomized controlled trials concurrently in six districts of Japan (Hokkaido, Tohoku, Kanto, Chubu, Kinki, and Nishi-Nihon) from 1992 through 1995. In Tohoku, Kanto, and Chubu, three-arm trials were designed to compare the surgery alone group, the surgery plus UFT group (UFT group), and the surgery plus tamoxifen group (TAM group). In Hokkaido, Kinki, and Nishi-Nihon, trials were based on a four-arm design, including an additional surgery plus TAM and UFT group (UFT plus TAM group; Fig 1).
Eligibility Criteria
Outlines of the six trials, which were previously unpublished, are listed in Table 1. All six trials had the same eligibility criteria. Eligible patients had to have histologically confirmed node-negative invasive breast cancer, have clinically measurable lesions 5 cm in diameter, adequate organ function, have undergone mastectomy with axillary node dissection, and be 75 years old. Patients with a history of other cancer therapy (radiotherapy, chemotherapy, endocrine therapy, immunotherapy, and so on) and those with multiple cancers were excluded. Fully informed consent was obtained from all patients before enrollment.
Random Assignment
Patients who met the eligibility criteria were enrolled at a registration center established for each trial. Random assignment was performed by the minimization method12 to ensure that the study groups were comparable with respect to tumor diameter ( 2 v > 2 to 5 cm), estrogen receptor (ER) status (positive v negative v unknown), and age (< 50 v 50 years). The randomization scheme described by Zelen13 was used to adjust for differences among six centers.
Treatment
Patients assigned to receive surgery alone were observed after operation, with no further treatment. Those in the UFT group received 300 mg/d of UFT (or 400 mg/d only in the Hokkaido group) for 2 years, starting within 4 weeks after operation. Patients assigned to the TAM group received 20 mg/d of TAM for 2 years regardless of the ER status. Patients in the UFT plus TAM group received 300 mg/d of UFT (or 400 mg/d only in the Hokkaido group) plus 20 mg/d of TAM for 2 years. In all groups, treatment according to protocol was discontinued on detection of recurrence, and other therapy could be initiated.
Follow-Up
The presence or absence of recurrence was confirmed at regular intervals at each center on the basis of the results of physical examination, chest x-ray films, imaging trials (ultrasonography or computed tomography scan) of the liver, and bone scintigraphic examination.
Adverse reactions were graded according to the WHO toxicity scale. Follow-up surveys were performed in 2002, after at least 6 years had passed since registration in all patients.
ER and DNA Ploidy Determinations
ER status was determined at each center. Either biochemical (enzyme immunoassay) or immunohistochemical techniques could be used.
In some patients, the DNA ploidy pattern of resected tumor tissues was analyzed by flow cytometry. Specimens of each primary breast cancer were frozen in liquid nitrogen in the operating room, and a suspension of isolated nuclei was prepared for DNA ploidy analysis as described by Vindelov et al.14 The suspensions were analyzed with an EPICS MCL-XL flow cytometer (Beckmann Coulter, Miami, FL) interfaced with a computer system (Multiplus; Phoenix Flow Systems, San Diego, CA). Tumors with the G0/G1 and G2/M peaks on the DNA histogram were defined as diploid tumors, and those with a clearly distinct additional peak from the G0/G1 and G2/M peaks were defined as aneuploid tumors. The DNA ploidy pattern was evaluated by an independent panel.
Pooled Analysis
This study consisted of pooled analysis of six randomized controlled trials carried out at the same time and with the same concept in the ACETBC trial groups, and no study was excluded. From February 1992 through April 1995, a total of 2,934 patients were registered. The median duration of observation was 6.2 years. Data from all registered patients were centrally analyzed according to the intention to treat. All analyses were based on individual patient data. Treatment effects were first estimated within each trial and then combined.
The 2 test, Mann-Whitney U test, two sample t test, and analysis of variance were used to determine the statistical significance of differences in baseline characteristics among the treatment groups. Overall survival, the primary end point of the study, was defined as the length of time from surgery to death as a result of any cause. Data on patients who were alive at the time of follow-up were censored. Cumulative 5-year survival rates were estimated according to the Kaplan-Meier method.
A Cox proportional hazards model was used to evaluate response in the drug-treated groups relative to that in the surgery alone group, adjusted for the following variables as covariates: tumor diameter ( 2 v > 2 to 5 cm), ER status (positive v negative v unknown), and age (< 50 v 50 years).
In addition, the overall effect of UFT (surgery alone plus TAM group v UFT group and UFT plus TAM group) and the overall effect of TAM (surgery alone plus UFT group v TAM group and UFT plus TAM group) were analyzed according to the Peto method15 on the basis of odds reduction, after excluding data on the TAM group in the three-arm trials and data on the UFT group in the three-arm trials, respectively. The overall effect of treatment was assessed through a 21 and the heterogeneity between trials through a 2n–1. Tests for interaction were used to detect departures from the homogeneity of treatment effects. Differences between groups in Kaplan-Meier estimates were evaluated with the log-rank test. Relation between rate of first recurrence and treatment were analyzed with the 2 test.
All data were analyzed using SAS software (version 6.12; SAS Institute, Cary, NC). All P values were calculated with two-tailed tests. The significance level was set at 5% for all tests of main effects and 10% for all tests of interaction or heterogeneity.
RESULTS
Comparison of Overall Survival Between Control, UFT, TAM, and UFT Plus TAM Groups
In total, 2,934 patients were analyzed in this pooled analysis including 860 patients in the control group, 860 patients in the UFT group, 865 patients in the TAM group, and 349 patients in the UFT plus TAM group. There was no significant difference in the distribution of clinicopathologic background factors among these four groups (Table 2). The 5-year survival rates were 93.4% for the control group, 96.0% for the UFT group, 95.0% for the TAM group, and 95.7% for the UFT plus TAM group (Fig 2A). Multivariate analysis has shown that the relative risks, taking the risk of the control group as reference, were 0.60 (95% CI, 0.39 to 0.94) for the UFT group, 0.73 (95% CI, 0.48 to 1.11) for the TAM group, and 0.62 (95% CI, 0.34 to 1.14) for the UFT plus TAM group (Table 3).
In the ER-positive subset, 5-year survival rates were 93.5% for the control group, 96.0% for the UFT group, 96.9% for the TAM group, and 98.0% for the TAM plus UFT group (Fig 2B). Multivariate analysis showed that the relative risks were 0.61 (95% CI, 0.33 to 1.13) for the UFT group, 0.44 (95% CI, 0.22 to 0.86) for the TAM group, and 0.28 (95% CI, 0.085 to 0.93) for the TAM plus UFT group (Table 3). In the ER-negative subset, 5-year survival rates were 93.2% for the control group, 95.8% for the UFT group, 93.9% for the TAM group, and 92.8% for the UFT plus TAM group (Fig 2B). Multivariate analysis showed that the relative risks to be 0.59 (95% CI, 0.29 to 1.20) for the UFT group, 0.89 (95% CI, 0.47 to 1.89) for the TAM group, and 1.05 (95% CI, 0.48 to 2.30) for the UFT plus TAM group (Table 3).
Comparison of Overall Survival Between UFT and Non-UFT Groups
We compared overall survival between the UFT group (UFT group and UFT plus TAM group) and the non-UFT group (control group plus TAM group). There was no significant difference in the clinicopathologic background factors between the UFT and the non-UFT groups (Table 4). A significant difference (log-rank test P = .04) was observed in 5-year survival rates between the UFT (95.9%) and the non-UFT (94.0%) groups (Fig 3). The odds reduction by UFT was 35% ± 16%, and no significant heterogeneity was observed among the six trials (Fig 4). In the UFT group, 32 patients died as a result of breast cancer, four died as a result of other types of cancer, and eight died as a result of noncancer diseases. In the non-UFT group, 52 died as a result of breast cancer, nine died as a result of other types of cancer, and five died as a result of noncancer disease. The first recurrent sites are shown in Table 5. The incidence of visceral metastases was significantly (2 test P = .01) lower in the UFT group than the non-UFT group. The subset analysis showed that the effect of UFT was more prominent in patients younger than 50 years (odds reduction, 48%; SD, ± 24%; P = .08) or older than 65 years (odds reduction, 48%; SD, ± 25%; P = .06), and in patients with tumor more than 2 cm in greatest dimension (odds reduction, 37%; SD, ± 18%; P = .06) or with DNA aneuploid tumors (odds reduction, 57%; SD, ± 28%; P = .04), or without TAM (odds reduction, 39%; SD, ± 17%; P = .025; Fig 5). However, interaction tests did not show any significant relationship between those subsets and the therapeutic effectiveness of UFT.
Comparison of Overall Survival Between TAM and Non-TAM Groups
Overall survival was compared between the TAM group (TAM group and UFT plus TAM group) and the non-TAM group (control group plus UFT group). There was no significant difference in the clinicopathologic background factors between the TAM and the non-TAM groups (Table 6). The 5-year survival rate (95.2%) in the TAM group was not significantly different from that (93.9%) in the non-TAM group (Fig 6). In the TAM group, 42 died as a result of breast cancer, three died as a result of other types of cancer, and six died as a result of noncancer diseases. In the non-TAM group, 53 died as a result of breast cancer, nine died as a result of other types of cancer, and five died as a result of noncancer diseases. The first recurrent sites are shown in Table 7. The soft tissue recurrence rate (2.6%) in the TAM group was lower, but not significantly (2 test P = .12) than in the non-TAM group (3.8%). The odds reduction by TAM was 27% (SD, ± 16%), and heterogeneity was not observed among the six trials (Fig 7). Subset analysis showed a significant odds reduction (54%; SD, ± 20%; log-rank test P = .01) in the ER-positive subset but not in the ER-negative subset (2%; SD, ± 27%; log-rank test P = .95), and also that the odds reduction was most prominent in the subset of patients older than 65 years (odds reduction, 45%; SD, ± 25%; P = .08; Fig 8).
Adverse Reactions
Table 8 lists the adverse reactions. The adverse reactions data in the control (surgery alone) group were not included in the table because we had performed a pooled analysis and were looking primarily at effectiveness; thus, we do not have sufficient data on the adverse events in the control group. There were 750 patients with adverse reactions in the UFT group, 743 in the TAM group, and 294 in the UFT plus TAM group, whereas the frequency of grade 2 WHO adverse reactions was 19.5% in the UFT group, 7.8% in the TAM group, and 20.4% in the UFT plus TAM group. Main adverse reactions were liver dysfunction in the TAM group, and liver dysfunction, anorexia, nausea, and vomiting in the UFT group. No increase in toxicity was found in the UFT plus TAM group compared with the UFT group, no increase in toxicity was found in the combined UFT and TAM groups, and there was no thrombosis or severe adverse reactions in any group.
DISCUSSION
One noteworthy observation in the present study is the confirmation of a fairly good prognosis of Japanese node-negative breast cancer patients in the control (surgery alone) group (5-year survival rate, 93.4%) compared with white counterparts (5-year survival rate, approximately 80%). The indications of adjuvant chemotherapy are usually decided on the basis of careful consideration of its risk-benefit balance. Patients with good prognosis can achieve only a small gain in absolute survival rate compared with those with poor prognosis, although the incidence and severity of adverse effects are similar in both groups. Thus, the indication of adjuvant chemotherapy for patients with good prognosis should be considered carefully. In this respect, Japanese node-negative breast cancer patients might be treated somewhat differently from white counterparts with regard to adjuvant chemotherapy.
Recently, oral fluoropyrimidines such as capecitabine (which has been reported to show a higher response rate [30%] than CMF [16%] in metastatic breast cancer patients16) have attracted attention for the treatment of metastatic breast cancer. This observation, taken together with the advantage that capecitabine rarely causes grade 3 to 4 neutropenia, has prompted the use of capecitabine in the adjuvant setting for older women. Actually, Cancer and Leukemia Group B 49907, which is comparing capecitabine with AC or CMF in women older than 65 years, is being conducted in the adjuvant setting for breast cancer. It is of note that the response rate of UFT in the metastatic setting is 30%, which is comparable with reported effectiveness of capecitabine,7,8 and that UFT has a relatively safer profile with regard to adverse reactions in general, and hand-foot syndrome, which appears frequently with capecitabine,17 in particular. These profiles seem to make UFT more appealing in the adjuvant setting.
In addition, we should bear in mind that our study involved much longer periods of administration than the six cycles of 21 days each that are being employed for capecitabine in the adjuvant setting in the ongoing trial (CALGB 49907). However, the administration period of capecitabine in that trial may have been set in accordance with the condition of the control arm of that study, and therefore there is room for doubt about whether six cycles would be optimal for capecitabine administration in an adjuvant setting. Moreover, the failure of 5'-deoxy-5-fluorouridine, which is an intermediate metabolite of capecitabine equipotent to UFT in metastatic disease,18 to demonstrate a survival benefit over surgery alone in Japanese node-negative breast cancer patients may be attributable to the shorter treatment period of 6 months in the adjuvant setting.19
The period of administration of UFT in all six studies was 2 years. The optimal duration of UFT in an adjuvant setting has not been fully clarified, but it is thought that it is necessary to administer it for more than 1 year to maximize benefits.9 The daily dose ranged from 300 to 400 mg in our study. Recently, positive data20 have been presented regarding UFT given in an adjuvant setting to stage I resected adenocarcinoma of the lung, and in that study the dosage of UFT was 260 mg/m2/d (approximately 400 mg/d) for 2 years. On the basis of our results, we recommend dosages of 300 to 400 mg/d.
UFT has been shown to significantly improve the relapse-free survival rates of stage I to IIIA breast cancer patients in the third ACETBC trial.9 Consistent with previous studies, in our pooled analysis of six randomized trials in which only node-negative breast cancer patients were recruited, patients treated with UFT had a significantly (P = .03) better survival rate (96.0%) than the controls (surgery alone; 93.4%). Given that UFT has milder adverse effects than AC and CMF,10,11 UFT may be more suited for the adjuvant treatment of node-negative breast cancer patients.
In ER-positive breast cancer patients, TAM treatment resulted in a significant (P = .02) improvement in survival in comparison with the control (surgery alone), as has been shown repeatedly in previous trials.21 Interestingly, although there was no significant difference, addition of UFT to TAM further improved the 5-year survival rates of ER-positive breast cancer patients (98.0% in the UFT plus TAM group v 96.9% in the TAM group).
Recently, Albain et al22 reported that the outcome of patients treated with concurrent CAF and TAM in the adjuvant setting is significantly poorer than those treated with sequential CAF and TAM, suggesting that TAM might inhibit the antitumor activity of CAF. However, our pooled analysis revealed that UFT has additive effects when given concurrently with TAM. Similarly, the National Surgical Adjuvant Breast and Bowel Project B-20 trial reported that concurrent chemotherapy (CMF, and methotrexate and FU [MF]) plus TAM showed a significantly better survival than TAM alone.23 These inconsistent results seem to suggest that the inhibitory effect of TAM on the antitumor activity of chemotherapy, if any, might depend on the type or duration of chemotherapy.
Comparison of the UFT and non-UFT groups has shown that UFT treatment results in a reduction of relative risk of death by 35%, mainly due to the reduction of visceral metastases, even in Japanese node-negative breast cancer patients who have a fairly good prognosis. Fisher et al24 studied the effect of adjuvant CMF or MF on relapse-free survival in breast cancer patients with good prognosis (node-negative and tumor size < 1 cm) and showed that these adjuvant chemotherapies could significantly improve the relapse-free survival. The 5-year survival rate of the control group of the study by Fisher et al24 was more than 90%—similar to that in our study. Thus, these results indicate that adjuvant chemotherapy is able to improve the survival of breast cancer patients even though they may already have a fairly good prognosis. However, the absolute gain in survival achieved by adjuvant chemotherapy in these patients is relatively small; that is, a 1.9% gain of 5-year survival rate in our study and a 5% gain of 8-year survival rate in the study by Fisher et al24 (chemotherapy plus TAM group v TAM group), and thus, the indications of adjuvant chemotherapy should be carefully selected considering the possibility of adverse effects.
The subset analysis showed that UFT was more effective in tumors measuring more than 2 cm and in aneuploid tumors, suggesting that the risk reduction by UFT is more prominent in tumors with a high risk for recurrence. Another important finding in this study was the demonstration of the usefulness of UFT in patients older than 65 years. However, interaction tests did not show significant differences between these results, and because these are the results of subset analysis, care is required in their interpretation. Randomized trials including a large number of elderly patients (older than 65 years) with node-negative breast cancer have not been conducted sufficiently, thus the indications of adjuvant chemotherapy for these patients are still controversial. In this respect, our study is valuable in that it includes more than 500 patients older than 65 years. Given that UFT shows milder adverse effects than AC and CMF, and because it is reported that 85% of patients opt for oral antitumor agents for chemotherapy rather than intravenous chemotherapy if the efficacy is the same,25 UFT seems to have the potential to be the treatment of choice as the adjuvant therapy for node-negative breast cancer patients, especially for elderly patients in whom dose reduction of AC and CMF is more frequently necessitated due to the adverse effects (eg, neutropenia) than in younger patients.26 Conversely, dose reduction and treatment cessation due to adverse effects are unlikely even in elderly women (older than 65 years) in adjuvant UFT. Currently, a randomized trial (National Surgical Adjuvant Study BC01) comparing UFT with CMF is ongoing in the adjuvant treatment of node-negative breast cancer patients in Japan.11,27 The results of this study together with the CALGB 49907 trial comparing capecitabine with AC or CMF in elderly patients will help to address the role of adjuvant oral fluoropyrimidines in the adjuvant setting.
When this trial was initiated in 1992, it was not established that 5-year TAM was better than 2-year TAM. It was also unclear whether TAM would be effective in ER-negative breast cancer patients; thus, TAM was given regardless of the ER status for 2 years in this study. Consistent with the Early Breast Cancer Trialists' Collaborative Group overview,21 this study has shown that TAM can improve the survival in ER-positive but not ER-negative breast cancer patients. At present, 5-year administration of TAM is considered to be standard care. If 5 years of TAM had been set as a parameter in our study, it is possible that there could have been a significant improvement in the overall survival with TAM. The data from the studies reported in this article cannot incontrovertibly determine whether UFT has additive effect on 5 years of TAM administration, or whether UFT has additive effects on aromatase inhibitors, which may be superior in the adjuvant setting to TAM 28 and is likely to be used increasingly in the future. These issues need to be clarified in a future study.
In conclusion, this pooled analysis has shown that adjuvant UFT can improve the overall survival in node-negative breast cancer patients, and UFT and TAM have the additive positive effects on a survival. Given that UFT has milder adverse effects than AC or CMF, it is suggested that UFT can be a useful alternative to AC or CMF in node-negative breast cancer patients, especially in elderly patients. In addition, in the metastatic setting, concomitant use of docetaxel and capecitabine has been proven to significantly prolong the survival time compared with a single use of docetaxel29; thus, oral fluoropyrimidines seem to have potential to further improve the survival of node-positive breast cancer patients who are treated with adjuvant sequential anthracycline and taxane therapy if fluoropyrimidine is given concurrently with or sequentially to the anthracycline and taxane therapy. This possibility also needs to be investigated in a future study.
Appendix
The following institutions participated in the study. Hokkaido region: First Department of Surgery, Hokkaido University School of Medicine; National Sapporo Hospital; Department of Surgery, Sapporo City General Hospital; Department of Surgery, Iwamizawa Municipal General Hospital; Department of Surgery, Otaru City Hospital; Department of Surgery, Tomakomai City General Hospital; Sapporo-Kosei General Hospital; Sapporo Social Insurance General Hospital; Kohnan Hospital; Department of Surgery, Caress Alliance Tenshi Hospital; Department of Surgery, Nikko Memorial Hospital; Kaisei Hospital; Hokkaido Keiaikai Minami 1-Jyo Hospital; Keiwakai Ebetsu Hospital; Hokuoh Hospital; Department of Surgery, Kucchan-Kosei General Hospital; Tonan Hospital, Federation of National Public Service and Affiliated Personnel Mutual Aid Associations; Shin-Nittetsu Muroran General Hospital; Oji General Hospital; First Department of Surgery, Sapporo Medical University, School of Medicine; Department of Surgery, Sapporo Tetsudo (JR) Hospital; Higashi Sapporo Hospital; Second Department of Surgery, Asahikawa Medical College; Asahikawa City Hospital; Takikawa Municipal Hospital; Fukagawa City Hospital; Department of Surgery, Akabira City General Hospital; Department of Surgery, Asahikawa-Kohsei Hospital; Department of Surgery, Kushiro City General Hospital; Nakashibetsu Town Hospital; Department of Surgery, Kitami Red Cross Hospital; Abasiri-Kosei General Hospital; Department of Surgery, Obihiro-Kosei General Hospital; Department of Surgery, Kushiro Rosai Hospital; Department of Surgery, National Hakodate Hospital; Department of Surgery, Hakodate Central General Hospital; Hakodate Medical Association Hospital.
Tohoku region: First Department of Surgery, Hirosaki University School of Medicine; Second Department of Surgery, Hirosaki University School of Medicine; Hirosaki Hospital; Aomori Prefectural Central Hospital; Hachinohe Red Cross Hospital; Department of Surgery, Aomori City Hospital; Department of Surgery, Hirosaki City Hospital; Aomori-Rosai Hospital; Seihoku Central Hospital; Hachinohe City Hospital; Department of Surgery I, Iwate Medical University; Iwate Prefectural Kitakami Hospital; Division of Surgery, Kitakami Saiseikai Hospital; Second Department of Surgery, Akita University School of Medicine; Hiraka General Hospital; Akita City General Hospital; Nakadori General Hospital; Japanese Red Cross Akita Hospital; Gastroenterological and General Surgery, Department of Organ Function and Controls, Yamagata University School of Medicine; Yamagata Prefectural Central Hospital; Department of Surgery, Municipal Sakata Hospital; Yamagata Prefectural Shinjo Hospital; Okitama Nagai Public Hospital; Yonezawa City Hospital; Division of Gastroenterological Surgery, Graduate School of Medicine Tohoku University; Division of Biologic Regulation and Oncology, Graduate School of Medicine Tohoku University; Division of Advanced Surgical Science and Technology, Graduate School of Medicine Tohoku University; Division of Surgical Oncology, Graduate School of Medicine Tohoku University; Sendai National Hospital; Kesennuma Public Hospital; Miyagi Cancer Center; Miyagi Social Insurance Hospital; Katta Hospital; Shizugawa Public Hospital; Sendai City Hospital; Tohoku Rosai Hospital; Sanuma General Hospital; Department of Surgery, Ishinomaki Red Cross Hospital; Tohoku Welfare Pension Hospital; Furukawa City Hospital; Department of Surgery II, Fukushima Medical University School of Medicine; Ohara General Hospital; Hoshi General Hospital.
Kanto region: Breast Division Department of Surgery School of Medicine, Keio University; Digestive Surgery, Tokyo Medical and Dental University; Third Department of Surgery, Nihon University School of Medicine; Department of Surgery, Tokyo Medical Women's University; Department of Surgery, Tokyo Women's Medical University Daini Hospital; Third Department of Surgery, Tokyo Medical University; Department of Surgery, Jikei University School of Medicine; Department of Surgery, Kyorin University School of Medicine; Ome Municipal General Hospital; Department of Endocrine Surgery, Toranomon Hospital; Kosei General Hospital; Saiseikai Central Hospital; Kitasato Institute Hospital; Department of Endocrine Surgery, Nippon Medical School; Department of Breast and Endocrine Surgery, Juntendo University School of Medicine; Breast and Endocrine Toho University School of Medicine; The Third Department of Surgery Toho University School of Medicine; Tokyo Kosei-Nenkin Hospital; Toshiba Hospital; Tokyo Metropolitan Hiroo General Hospital; Tokyo Kyosai Hospital; Mitsui Memorial Hospital; Kyosai Tachikawa Hospital; National Tokyo Medical Center; Department of Surgery, Kanto Medical Center NTT EC; Department of Surgery, The Jikei Daisan-Hospital; Japanese Red Cross Medical Center; Department of Breast Surgery, Nippon Medical School; Department of Surgery, The Jikei University School of Medicine, Aoto Hospital; Tokyo Metropolitan Fuchuu Hospital; First Department of Surgery, Nihon University School of Medicine; Edogawa Hospital; Akiru Municipal General Hospital; St Luke's International Hospital; Tokyo Electric Hospital; Keiyu Hospital; Department of Surgery, Tokai University School of Medicine; Showa University Fujigaoka Hospital; Hiratsuka City Hospital; Division of Breast and Endocrine Surgery Department of Surgery, St Marianna University School of Medicine; Department of Surgery, Kitasato University School of Medicine; Yokosuka Kyosai Hospital; Nippon Koukan Hospital; Kanto Rosai Hospital; Sagamihara National Hospital; National Yokohama Medical Center; Fujisawa Municipal Hospital; Kanagawa Cancer Center Hospital; St Marianna University School of Medicine Toyoko Hospital; Yamato Municipal Hospital; Yokohama Minami Kyosai Hospital; Nippon Medical School Second Hospital; Isehara Kyodo Hospital; Department of Surgery, Saiseikai Yokohama City Southern Hospital; Saiseikai Kanagawaken Hospital; Seirei Yokohama Hospital; St Marianna University Yokohama City Seibu Hospital; Odawara Municipal Hospital; Sagamihara Kyodo Hospital; Teikyo University Mizonokuchi Hospital; Yokohama Sakae Kyosai Hospital; Yokohama Red Cross Hospital; Department of Academic Surgery, Chiba University Graduate School of Medicine; Department of Surgery, Kameda General Hospital; Department of General Surgery, Chiba University Graduate School of Medicine; Department of Surgery, Matsudo Municipal Hospital; Department of Surgery, Teikyo University School of Medicine Ichihara Hospital; Kohnodai Hospital, National Center of Neurology and Psychiatry; Department of Surgery, Chiba Rousai Hospital; Department of Surgery, Jikei University Kashiwa Hospital; Department of Surgery, Sakura Hospital Toho University School of Medicine; Second Department of Surgery, Saitama Medical School; Division of Breast Surgery, Saitama Cancer Center; Kasukabe Municipal Hospital; Saitama Social Insurance Hospital; National Saitama Hospital; Saitama Red Cross Hospital; First Department of Surgery, Saitama Medical School; Koshigaya Municipal Hospital; Koshigaya Hospital Dokkyo University School of Medicine; Ageo Central General Hospital; Souka Municipal Hospital; Gunma Prefectural Cancer Center; Takasaki National Hospital; National Nishigunma Hospital; Sano Kousei General Hospital; First Department of Surgery, Dokkyo University School of Medicine; Ashikaga Red Cross Hospital; Haga Red Cross Hospital; Kamitsuga General Hospital; Department of Surgery, Tochigi Cancer Center; Department of Surgery, Mito Red Cross Hospital; Department of Surgery, Mito National Hospital; Department of Surgery, Toride Kyodo General Hospital; The First Department of Surgery, Faculty Medicine University of Yamanashi; The Second Department of Surgery, Faculty Medicine University of Yamanashi; Ojiya General Hospital; Department of Surgery, Shizuoka Red Cross Hospital.
Chubu region: The Second Department of Surgery, Nagoya University School of Medicine; The Second Department of Surgery, Nagoya City University Medical School; Department of Surgery, School of Medicine Fujita Health University; The First Department of Surgery, Aichi Medical University; National Nagoya Hospital; Second Teaching Hospital School of Medicine Fujita Health University; Department of Surgery, Nagoya First Red Cross Hospital; Department of Surgery, Nagoya Second Red Cross Hospital; Johoku Municipal Hospital; Higashi Municipal Hospital of Nagoya; Kasugai Municipal Hospital; Toyohashi Municipal Hospital; Department of Surgery, Toyokawa City Hospital; Okazaki City Hospital; Nishio Municipal Hospital; Nagoya Ekisaikai Hospital; Seirei Hospital; Chubu Rosai Hospital; Department of Surgery, NTT West Corporation Tokai General Hospital; Tosei General Hospital; Department of Surgery, Kamo Hospital; Toyota Memorial Hospital; Showa Hospital; Moriyama Municipal Hospital, City of Nagoya; Department of Surgery, Gamagori City Hospital; Department of Surgery, Anjo Kosei Hospital; Department of Surgery, Chita City Hospital; Department of Advanced Surgery, Gifu University School of Medicine; Department of Surgical Oncology, Gifu University School of Medicine; Department of Surgery, Gifu Prefectural Gifu Hospital; Gifu Prefectural Tajimi Hospital; Department of Surgery, Ogaki Municipal Hospital; Department of Surgery, Gifu Municipal Hospital; Department of Surgery, Kumiai Hospital; Department of Surgery, Ibi General Hospital; Department of Surgery, Toki General Municipal Hospital; Department of Surgery, National Matsumoto Hospital; Department of Surgery, Nagano Red Cross Hospital; Department of Surgery, Okaya Enrei Hospital; Department of Surgery, Komoro Kosei Hospital; Department of Surgery, Iida Municipal Hospital; Showa Inan Hospital; Department of Surgery, Nagano Chuo Hospital; Department of Surgery, Iiyama Red Cross Hospital; Department of Surgery, Nagano Prefectural Welfare Federation of Agricultural Cooperatives Hokushin General Hospital; Department of Surgery, Toyoshina Red Cross Hospital; The First Department of Surgery, Faculty of Medicine, Mie University; The Second Department of Surgery, Faculty of Medicine, Mie University; Department of Surgery, National Mie Chuo Hospital; Department of Surgery, Yamada Red Cross Hospital; Department of Surgery, Matsusaka Chuo General Hospital; Mie Prefectural Shima Hospital; Department of Surgery, Ise Municipal General Hospital; Department of Surgery, Yokkaichi Municipal Hospital; Department of Surgery, Matsusaka City Hospital; The Department of General Surgery, Suzuka General Hospital; Department of Surgery, Saiseikai Matsusaka General Hospital; Yamamoto General Hospital; Department of Surgery, Yokkaichi Social Insurance Hospital; First Department of Surgery, Hamamatsu University School of Medicine; Tosei National Hospital; Department of Surgery, Shizuoka General Hospital; Fukuroi Municipal Hospital; Yaizu City Hospital; Hamamatsu Medical Center; Fuji City General Hospital; Seirei mikatahara Hospital; Seirei Hamamatsu General Hospital; Ensyu General Hospital; Shizuoka Kosei General Hospital; Seirei Numazu Hospital; Fujinomiya City General Hospital; Second Department of Surgery, Toyama Medical and Pharmaceutical University; Kurobe City Hospital; Department of Surgery, Kouseiren Takaoka Hospital; Tonami General Hospital; Department of Surgery (I), Kanazawa University School of Medicine; Department of Surgery II, Kanazawa University Hospital; Kanazawa Social Insurance Hospital; Kanazawa Social Insurance Hospital; Department of Surgery II, University of Fukui; Fukui Red Cross Hospital; Fukui Prefectural Hospital; First Department of Surgery, Faculty of Medicine, University of Fukui.
Kinki region: Second Department of Surgery, Osaka City University Medical School; Department of Surgery E1, Osaka University Graduate School of Medicine; Department of Surgery and Clinical Oncology, Osaka University Graduate School of Medicine; Department of Surgical Oncology, Osaka University Graduate School of Medicine; Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases; Department of General and Gastrointestinal Surgery, Osaka Medical College; Osaka Kaisei Hospital; Osaka Police Hospital; Osaka Seamen's Insurance Hospital; Osaka Railway Hospital of West Japan Company; Osaka Red Cross Hospital; Osaka General Medical Center; Osaka Rosai Hospital; Department of Surgery, Kansai Medical University; Kitano Hospital; Osaka National Hospital; Hanwadainisenboku Hospital; PL Hospital; Nissay Hospital; Ikeda Municipal Hospital; Sakai Municipal Hospital; Toyonaka Municipal Hospital; Higashiosaka City General Hospital; Minoh City Hospital; Yao Municipal Hospital; Yodogawa Christian Hospital; Wakayama Medical University Surgery I; Wakayama Rosai Hospital; Department of Surgical Oncology, Osaka City University Graduate School of Medicine; Saiseikai Tondabayasi Hospital; Rinku General Medical Center; Sakai Hospital, Kinki University School of Medicine; Mimihara General Hospital; Kaizuka City Hospital; Kishiwada City Hospital; Bell Land General Hospital; Otemae Hospital; Minami Wakayama National Hospital; Hirakata City Hospital; Hanwasumiyoshi General Hospital; First Department of Surgery, Hyogo College of Medicine; Hyogo College of Medicine Second Department of Surgery; Hyogo Prefectural Amagasaki Hospital; Hyogo Prefectural Tsukaguchi Hospital; Hyogo Prefectural Nishinomiya Hospital; Nishinomiya Municipal Central Hospital; Kansai Rosai Hospital; Kawanishi City General Hospital; Kobe City General Hospital; Konan Hospital; Shinko Hospital; Department of Gastroenterological Surgery Graduate School of Medical Sciences Kobe University; National Kobe Hospital; Kobe West City Hospital; Akashi Municipal Hospital; Kawasaki Hospital; National Himeji Hospital; Hyogo Prefectural Kakogawa Hospital; Takasago Municipal Hospital; Ako City Hospital; Toyooka Hospital; Kinki Central Hospital of The Mutual Aid Association of Public School Teachers; Kobe Ekisaikai Hospital; Rokko Hospital; School of Health Sciences Faculty of Medicine Kyoto University; Kyoto Prefectural University of Medicine; Kyoto First Red Cross Hospital; Kyoto National Hospital; Department of Surgery, Kyoto City Hospital; Uji Hospital; Koseikai Takeda Hospital; National Maizuru Hospital; Nantan General Hospital; Fukuchiyama City Hospital; Kyoto Prefectural Yosanoumi Hospital; Kyoto Senbai Hospital; Maizuru Municipal Hospital; Federation of National Public Service Personnel Mutual Aid Associations Maizuru Kyosai Hospital; Department of Surgery, Shiga University of Medical Science; Nagahama City Hospital; First Department of Surgery, Nara Medical University; National Nara Hospital; Saiseikai Chuwa Hospital; Saiseikai Shiga Hospital; Kansai Medical University Otokoyama Hospital; Department of Breast and Thyroid Surgery, Kawasaki Medical School; Kurashiki Medical Center.
Nishi-Nihon region: Department of Surgery Division of Frontier Medical Science Program for Biomedical Research Graduate School of Biomedical Science Hiroshima University; Hiroshima Prefectural Hospital; Hiroshima Red Cross Hospital and Bomb Survivors Hospital; National Kure Medical Center; Hiroshima City Asa Hospital; Miyoshi Central Hospital; Fukuyama National Hospital; Department of Surgery Division of Clinical Medical Science Program for Applied Biomedicine Graduate School of Biomedical Science Hiroshima University; Department of Surgical, Oncology Research Institute for Radiation Biology and Medicine Hiroshima University; Hiroshima Municipal Hospital; Hiroshima General Hospital; Chugoku Central Hospital; Okayama Saiseikai General Hospital; Kurashiki Central Hospital; National Okayama Medical Center; Department of Gastroenterological Surgery, Transplant and Surgical Oncology, Okayama University Graduate School of Medicine and Dentistry; Department of Surgery, Division of Surgical Oncology, School of Medicine, Tottori University; Tottori Municipal Hospital; Yamaguchi Rosai Hospital; Shimonoseki National Hospital; Shiminoseki Kosei Hospital; Shimonoseki City Central Hospital; Iwakuni National Hospital; Department of Digestive Surgery and Surgical Oncology, Molecular Science and Applied Medicine, Yamaguchi University School of Medicine; Tagawa City Hospital; Saiseikai Yahata General Hospital; Department of Surgery and Science, Graduate School of Medical Science, Kyushu University; National Kyushu Cancer Center; First Department of Surgery, Fukuoka University School of Medicine; National Kyushu Medical Center; First Department of Surgery, Kurume University School of Medicine; Aso Iizuka Hospital; Syakaihoken Nakabaru Hospital; Fukuoka City Hospital; Fukuoka-Higashi National Hospital; Munakata Medical Association Hospital; Saga Prefectural Hospital Kouseikan; Department of Transplantation and Digestive Surgery Nagasaki University Graduate School of Biomedical Sciences; National Nagasaki Medical Center; The Japanese Red Cross Nagasaki Atomic Bomb Hospital; Nagasaki Municipal Hospital; Division of Surgical Oncology, Department of Translational Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences; Division of Surgical Oncology, Kyushu University Hospital at Beppu; Oita Red Cross Hospital; Oita Prefectural Hospital; Department of Surgery II, Miyazaki Medical College; National Hospital Organization Miyakonojo Hospital; Miyazaki Prefectural Nichinan Hospital; Kumamoto Chuou Hospital; Saiseikai Kumamoto Hospital; Kumamoto Rousai Hospital; Minamata City General Hospital and Medical Center; Arao Municipal Hospital; Yamaga Municipal Hospital; Yatsushiro Health Insurance General Hospital; Kumamoto City Hospital; Tamana Central Hospital; Kanoya Medical Center Ctizens' Health Plaza; Department of Surgical Oncology and Digestive Surgery, Field of Oncology, Course of Advanced Therapeutics, Kagoshima University Graduate School of Medical and Dental Sciences; Saisekai Sendai Hospital; Unit of Organ-Oriented Medicine, Division of Digestive and General Surgery, Faculty of Medicine, University of The Ryukyus; Department of Bioregulatory Medicine, Thoracic and Cardiovascular Surgery Division, Faculty of Medicine, University of The Ryukyus; Okinawa Red Cross Hospital; Department of Oncological and Regenerative Surgery, School of Medicine, University of Tokushima; Tokushima City Hospital; Kagawa Prefectural Central Hospital; Takamatsu Red Cross Hospital; Surgery I, Ehime University Hospital; Matsuyama Red Cross Hospital; National Shikoku Cancer Center; Department of Surgery, Kochi Medical School; Kochi Red Cross Hospital; Kochi Municipal Central Hospital; Oikawa Hospital; Kitakyushu City Yahata Hospital; Department of Surgery II, University of Occupational and Environmental Health; Nippon Steel Yawata Memorial Hospital; Kitakyushu Municipal Medical Center, Japan.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Acknowledgment
We thank J. Patrick Barron of the International Medical Communications Center of Tokyo Medical University for his review of this manuscript.
NOTES
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
Early Breast Cancer Trialists' Collaborative Group: Polychemotherapy for early breast cancer: An overview of the randomised trials. Lancet 352:930-942, 1998
Henderson IC, Berry DA, Demetri GD, et al: Improved outcomes from adding sequential Paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21:976-983, 2003
Citron ML, Berry DA, Cirrincione C, et al: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 21:1431-1439, 2003
Nabholtz JM, Pienkowski T, Mackey T, et al: Phase III trial comparing TAC (docetaxel, doxorubicin, cyclophosphamide) with FAC (5-fluorouracil, doxorubicin, cyclophosphamide) in the adjuvant treatment of node positive breast cancer (BC) patients: Interim analysis of the BCIRG 001 study. Proc Am Soc Clin Oncol 21:35a, 2002 (abstr 137)
Mamounas EP, Bryant J, Lembersky BC, et al: Paclitaxel (T) following doxorubicin/cyclophosphamide (AC) as adjuvant chemotherapy for node-positive breast cancer: Results from NSABP B-28. Proc Am Soc Clin Oncol 22:4, 2003 (abstr 12)
Nemoto T, Tominaga T, Chamberlain A, et al: Differences in breast cancer between Japan and the United States. J Natl Cancer Inst 58:193-197, 1977
Ota K, Taguchi T, Kimura K: Report on nationwide pooled data and cohort investigation in UFT phase II study. Cancer Chemother Pharmacol 22:333-338, 1988
Tashiro H, Nomura Y, Ohsaki A: A double blind comparative study of tegafur (FT) and UFT (a combination of Tegafur and uracil) in advanced breast cancer. Jpn J Clin Oncol 24:212-217, 1994
Kasumi F, Yoshimoto M, Uchino J, et al: Meta-analysis of five studies on tegafur plus uracil (UFT) as post-operative adjuvant chemotherapy for breast cancer. Oncology 64:146-153, 2003
Tamura H, Kojima M, Kobayashi H, et al: Randomized comparative study of CMF (cyclophosphamide, methotrexate and 5-fluorouracil) and UFT-tamoxifen regimens as adjuvant chemotherapy after surgery for breast cancer: Tochigi Prefectural Study Group for Post-Breast Cancer Adjuvant Chemotherapy [in Japanese]. Gan To Kagaku Ryoho 27:993-1002, 2000
Shimozuma K, Ohashi Y, Watanabe T, et al: Impact of surgical adjuvant chemotherapy on health-related quality of life of patients with breast cancer in the first-year of treatment—A phase III randomized trial comparing uracil/tegafur with CMF in high-risk node-negative patients (N-SAS BC 01). Proc Am Soc Clin Oncol 22:55, 2003 (abstr 220)
Pocock SJ, Simon R: Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Biometrics 31:103-115, 1975
Zelen M: The randomization and stratification of patients to clinical trials. J Chronic Dis 27:365-375, 1974
Vindelov LL: Flow cytometric DNA analysis. Eur J Respir Dis 66:313-314, 1985
Early Breast Cancer Trialists' Collaborative Group: Treatment of Early Breast Cancer, Vol 1.1. Oxford, United Kingdom, Oxford University Press, 1990, pp 12-18
O'Shaughnessy JA, Blum J, Moiseyenko V, et al: Randomized, open-label, phase II trial of oral capecitabine (Xeloda) vs. a reference arm of intravenous CMF (cyclophosphamide, methotrexate and 5-fluorouracil) as first-line therapy for advanced/metastatic breast cancer. Ann Oncol 12:1247-1254, 2001
Blum JL, Jones SE, Buzdar AU, et al: Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 17:485-493, 1999
Niitani H, Kimura K, Saito T, et al: Phase II study of 5'-deoxy-5-fluorouridine (5'-DFUR) in patients with malignant cancer: A multi-institutional cooperative study [in Japanese]. Gan To Kagaku Ryoho 12:2044-2051, 1985
Tominaga T, Toi M, Abe O, et al: The effect of adjuvant 5'-deoxy-5-fluorouridine in early stage breast cancer patients: Results from a multicenter randomized controlled trial. Int J Oncol 20:517-525, 2002
Kato H, Ichinose Y, Ohta M, et al: A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N Engl J Med 350:1713-1721, 2004
Early Breast Cancer Trialists' Collaborative Group: Tamoxifen for early breast cancer: An overview of the randomised trials. Lancet 351:1451-1467, 1998
Albain KS, Green SJ, Ravdin PM, et al: Adjuvant chemohormonal therapy for primary breast cancer should be sequential instead of concurrent: Initial results from intergroup trial 0100 (SWOG-8814). Proc Am Soc Clin Oncol 21:37a, 2002 (abstr 143)
Fisher B, Dignam J, Wolmark N, et al: Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst 89:1673-1678, 1997
Fisher B, Dignam J, Tan-Chiu E, et al: Prognosis and treatment of patients with breast tumors of one centimeter or less and negative axillary lymph nodes. J Natl Cancer Inst 93:112-120, 2001
Borner MM, Schoffski P, de Wit R, et al: Patient preference and pharmacokinetics of oral modulated UFT versus intravenous fluorouracil and leucovorin: A randomised crossover trial in advanced colorectal cancer. Eur J Cancer 38:349-358, 2002
Crivellari D, Bonetti M, Castiglione-Gertsch M, et al: Burdens and benefits of adjuvant cyclophosphamide, methotrexate, and fluorouracil and tamoxifen for elderly patients with breast cancer: The International Breast Cancer Study Group Trial VII. J Clin Oncol 18:1412-1422, 2000
Watanabe T: Phase III randomized comparison of postoperative adjuvant chemotherapy with 2-year oral uracil/tegafur versus 6-cycle cyclophosphamide/methotrexate/5-fluorouracil in high-risk node-negative breast cancer patients. Cancer Chemother Pharmacol 42:S68-S70, 1998 (suppl)
Baum M, Budzar AU, Cuzick J, et al: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: First results of the ATAC randomised trial. Lancet 359:2131-2139, 2002
O'Shaughnessy J, Miles D, Vukelja S, et al: Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: Phase III trial results. J Clin Oncol 20:2812-2823, 2002(Shinzaburo Noguchi, Hirok)